The present invention provides oligomeric compounds and uses thereof. In certain embodiments, such oligomeric compounds are useful as antisense compounds. Certain such antisense compounds are useful as RNase H antisense compounds or as RNAi compounds.
대표청구항▼
1. An oligomeric compound comprising a single-stranded oligonucleotide consisting of 10-30 linked nucleosides, wherein the oligonucleotide comprises a phosphate stabilizing nucleoside at the 5′-end, wherein the phosphate stabilizing nucleoside comprises: i) a 5′-terminal modified phosphate; orii) a
1. An oligomeric compound comprising a single-stranded oligonucleotide consisting of 10-30 linked nucleosides, wherein the oligonucleotide comprises a phosphate stabilizing nucleoside at the 5′-end, wherein the phosphate stabilizing nucleoside comprises: i) a 5′-terminal modified phosphate; orii) a 5′-terminal unmodified phosphate and a modified sugar moiety comprising a 5′ modification; and a linking group linking the phosphate stabilizing nucleoside to the remainder of the oligonucleotide; and wherein the remainder of the oligonucleotide comprises at least one region having a nucleoside motif: (A)n-(B)n-(A)n-(B)n, wherein:A and B are differently modified nucleosides; andeach n is independently selected from 1, 2, 3, 4, and 5; oriii) both i) and ii). 2. The oligomeric compound of claim 1, wherein: the 5′-terminal modified phosphate is selected from: phosphonate, alkylphosphonate, substituted alkylphosphonate, aminoalkyl phosphonate, substituted aminoalkyl phosphonate, phosphorothioate, phosphoramidate, alkylphosphonothioate, substituted alkylphosphonothioate, phosphorodithioate, and thiophosphoramidate; andthe 5′-modification of the sugar moiety of the phosphate stabilizing nucleoside is selected from 5′-alkyl and 5′-halogen. 3. The oligomeric compound of claim 1, wherein the modified phosphate is selected from: phosphonate, alkylphosphonate, and substituted alkylphosphonate. 4. The oligomeric compound of claim 1, wherein A and B are each selected from: a 2′-F nucleoside, a 2′-OCH3 nucleoside, a 2′-O(CH2)2OCH3 nucleoside, a (4′-CH2—O-2′) BNA nucleoside, a (4′-(CH2)2—O-2′) BNA nucleoside, a (4′-CH(CH3)—O-2′) BNA nucleoside, a DNA nucleoside, an RNA nucleoside, and an F-HNA nucleoside. 5. The oligomeric compound of claim 1, wherein at least one of A and B is a 2′-F, 2′-OCH3 or 2′-O(CH2)2OCH3 nucleoside. 6. The oligomeric compound of claim 4, wherein A is a 2′-F nucleoside and B is a 2′-OCH3 nucleoside. 7. The oligomeric compound of claim 1 comprising a 3′-region consisting of from 1 to 5 nucleosides at the 3′-end of the oligomeric compound wherein: the nucleosides of the 3′-region each comprises the same modification as one another; andthe nucleosides of the 3′-region are modified differently than the last nucleoside adjacent to the 3′-region. 8. The oligomeric compound of claim 7, wherein the nucleosides of the 3′-region are 2′-O(CH2)2OCH3 nucleosides; and wherein the 3′-region consists of 2 linked nucleosides. 9. The oligomeric compound of claim 7, wherein each nucleoside of the 3′-region comprises a thymine base. 10. The oligomeric compound of claim 1, wherein the remainder of the oligonucleotide comprises at least one region of nucleosides having a motif I: Nf(PS)Nm(PO), wherein:Nf is a 2′-F nucleoside,Nm is a 2′-OCH3 nucleosidePS is a phosphorothioate linking group; andPO is a phosphodiester linking group. 11. The oligomeric compound of claim 10 comprising at least 2 regions of nucleosides having the motif I. 12. The oligomeric compound of claim 10 comprising at least 6 regions of nucleosides having the motif I. 13. The oligomeric compound of claim 10 comprising at least 7 regions of nucleosides having the motif I. 14. The oligomeric compound of claim 1 comprising one or more conjugate groups. 15. The oligomeric compound of claim 1 wherein the oligomeric compound is an RNAi compound. 16. A pharmaceutical composition comprising an oligomeric compound according to claim 1 and a pharmaceutically acceptable diluent or carrier. 17. A method comprising contacting a cell with an oligomeric compound according to claim 1. 18. The method of claim 17, wherein the cell is in vitro. 19. The method of claim 17, wherein the cell is in an animal. 20. The oligomeric compound of claim 1, wherein the phosphate stabilizing nucleoside comprises a 2′-modification selected from: halogen, allyl, amino, azido, thio, O-allyl, —O—C1-C10 alkyl, —O—C1-C10 substituted alkyl, —OCF3, —O—(CH2)2—O—CH3, —O(CH2)2SCH3, —O—(CH2)2O—N(Rm)(Rn), —O—CH2—C(═O)—N(Rm)(Rn), where each Rm and Rn is, independently, H or substituted or unsubstituted C1-C10 alkyl, —O[(CH2)nO]mCH3, —O(CH2)nNH2, —O(CH2)nCH3, —O(CH2)nONH2, —OCH2C(═O)N(H)CH3, —O(CH2)nON[(CH 2)nCH3]2, where n and m are from 1 to about 10; C1 to C10 alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH3, OCN, Cl, Br, CN, CF3, OCF3, SOCH3, SO2CH3, ONO2, NO2, N3, NH2, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl. 21. The oligomeric compound of claim 1, wherein the phosphate stabilizing nucleoside comprises a 5′ terminal modified phosphate and a modified sugar moiety comprising a 5′ modification. 22. The oligomeric compound of claim 21, wherein the phosphate stabilizing nucleoside comprises a 2′-modification selected from: halogen, allyl, amino, azido, thio, O-allyl, —O—C1-C10 alkyl, —O—C1-C10 substituted alkyl, —OCF3, —O—(CH2)2—O—CH3, —O(CH2)2SCH3, —O—(CH2)2—O—N(Rm)(Rn), —O—CH2—C(═O)—N(Rm)(Rn), where each Rm and Rn is, independently, H or substituted or unsubstituted C1-C10 alkyl, —O[(CH2)nO]mCH3, —O(CH2)nNH2, —O(CH2)nCH3, —O(CH2)nONH2, —OCH2C(═O)N(H)CH3, —O(CH2)nON[(CH2)nCH3]2, where n and m are from 1 to about 10; C1 to C10 alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH3, OCN, Cl, Br, CN, CF3, OCF3, SOCH3, SO2CH3, ONO2, NO2, N3, NH2, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl. 23. The oligomeric compound of claim 22, wherein the phosphate stabilizing nucleoside comprises a 2′-modification selected from: —F, —O—(CH2)2—O—CH3, and —OCH3.
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